Herpes virus infections in humans can be caused by different human and animal herpes viruses, the most common being herpes simplex virus and varicella-zoster virus.
Following a primary infection with herpes simplex or varicella-zoster virus, the virus establishes latency in the sensory nerve cells for the rest of the patient's life and subsequently repeated virus reactivation can occur. Following a reactivation in the nerve cell the virus is transported through the nerves to the skin and then a lesion will develop Immediately upon an outbreak of virus replication inflammation will follow. The inflammation contributes to the symptoms associated with herpes virus recurrence, including redness, swelling, itching and pain as well as lesions.
Herpes simplex viruses may be grouped into two serotypes, HSV type 1 (HSV-1) and type 2 (HSV-2), the clinical manifestations of which range from benign self-limiting orofacial and genital infections to potentially life threatening conditions such as encephalitis and generalized neonatal infections. Oral-facial HSV infections are primarily caused by HSV-1, which becomes latent after a primary infection e.g. in childhood. After reactivation a recurrent oral-facial HSV infection develops, more commonly known as a cold sore. About half of the patients experience early symptoms, e.g. pain, burning or itching at the site of the subsequent lesions. The condition is generally rapidly self-limiting and the healing time of a typical episode is about 10 days from the initial symptoms. Viral replication in the lip is initiated early and maximum virus load is attained 24 hours after the onset of the reactivation. The virus concentration is then dramatically reduced and typically virus cannot be isolated 70-80 hours after the onset.
The clinical presentation of genital HSV infections is similar to the oral-facial infections with some important exceptions. Genital HSV infections are most often caused by HSV-2 and following the primary infection the virus will latently infect sensory or autonomic ganglions. Reactivation will produce the local recurrent lesions on or near the genitals that are to characteristic of the herpes infection.
A primary infection with varicella-zoster virus (VZV) causes chicken-pox. Like HSV, VZV becomes latent following the primary infection and can be activated as herpes zoster later on in life. Zoster usually results in skin rash and intensive acute pain. In 30% of the patients, the pain can be prolonged and continue for weeks or months after the rash has cleared up, or may even be permanent.
HSV and VZV may, in addition to mucous or cutaneous manifestations, also cause keratitis in the eyes. This condition is also recurrent and may cause blindness.
There are a number of antiviral agents which are active against the human herpes viruses. However, so far clinical success in the treatment of recurrent herpes virus infections has been only limited and there still exists no cure for herpes.
Various antivirals are used with varying success, e.g.: acyclovir (aciclovir), valacyclovir (valacyclovir), famciclovir, and penciclovir. For example, a cream formulation of acyclovir for topical application is sold by Ranbaxy under the generic name Zovirax.
WO96/024355 describes a combination formulation for topical administration comprising a topically acceptable antiviral agent, e.g. acyclovir, and an antiinflammatory glucocorticoid, e.g. hydrocortisone. A composition within the scope of said patent application, useful for the topical treatment of recurrent herpes labialis (cold sores) is commercially available as Xerclear™ (Xerese™ in the USA). Said composition contains 5% acyclovir and 1% hydrocortisone in a cream formulation.
There however still remains a need for effective drugs and methods of treatment for primary as well as recurrent herpes infections.
B-220 was disclosed for the first time in the PCT application published as WO87/04436, which showed the antiviral effect of a number of indoloquinoxalines against herpes simplex virus of both type 1 and 2. The antiviral effect was shown by injecting the test substance in mice receiving also an intracerebral injection of the virus.
The antiviral activity of B-220 against human cytomegalovirus has also been mentioned in the PCT application published as WO07/084073, where B-220 is used as a reference compound in a modified plaque assay.